Administration of pharmaceuticals and other solid formulations via absorption in the oral cavity provide several advantages over administration via absorption from the gastrointestinal (GI) tract. Buccal (against the cheek) and sublingual (under the tongue) dosage forms of drugs can bypass first-pass metabolism that occurs in the intestine during absorption and in the liver immediately following absorption from the GI tract. Such first-pass metabolism results in reduction of available drug material. In addition, drug absorption in the oral cavity can result in a rapid onset of drug action because the oral cavity has a rich supply of blood vessels to transport the drug throughout the systemic circulatory system. Therefore, buccal/sublingual dosage forms can provide more biologically available drug and adequate plasma levels of a drug at lower initial administration dosage compared to drugs delivered via administration from the GI tract. Drugs absorbed within the oral cavity also are delivered systemically faster than drugs absorbed from the GI tract. In order to determine appropriate dosing for drug delivery via the oral cavity, it is important to quantify the time course of a drug's dissolution within the oral cavity. There is need in the art for devices that simulate the flow of saliva in the human mouth and the subsequent dissolution of drugs in the oral cavity. The present invention provides improved methods and apparatus for determining, in vitro, the dissolution of a solid compound placed within the oral cavity.
A number of sublingual dosage forms are available for pain control, heart conditions, asthma, antiemesis and treatment of drug abuse including, for example, nitroglycerine, subutex, suboxone and isoproterenol. Because of the advantages outlined above, further increase in formulations utilizing sublingual dosage forms is expected. An oral delivery route is a non-invasive means to deliver a wide variety of biotechnological or pharmaceutical products including, for example, proteins, peptides, oligonucleotides, siRNA and gene therapy compositions.
There are numerous in vitro apparatuses for testing dissolution of formulations in the gastro-intestinal (GI) tract. See, e.g. U.S. Pat. Nos. 5,639,974, 5,807,115, 6,060,024; U.S Pat. Pub. No. 2003/0235110; The United States Pharmacopeial Convention, USP 25. However, these systems are not suitable for assessing dissolution of solid formulations in the oral cavity. First, the GI apparatuses typically contain up to 900 mL of solution, agitated using either a paddle stirrer or a rotating basket assembly. For stirrer assemblies, the stirrer must be completely submerged in the dissolution fluid. Therefore, the minimum amount of fluid with which the dissolution vessel can be operable is about 450 mL. USP 25 recommends using 900 mL fluid for most studies. The fluid capacity and/or content of the human mouth is much less than 900 mL or even the minimum volume of 450 mL. In addition, the paddle and rotating basket-type assemblies produce considerable agitation of the dissolution medium. Such agitation suitably models peristaltic movement in the GI tract. However, because the oral cavity lacks peristaltic movement, such agitation is inappropriate for simulating dissolution within the oral cavity.
The fluid dynamics of the apparatuses that model GI-tract dissolution are also inappropriate for modeling dissolution within the oral cavity. Such GI apparatuses are closed systems in that the dissolution medium does not continuously enter and leave the vessel. Generally, samples are withdrawn from the vessel at different time intervals and the vessel contents may or may not be replenished by fresh medium. The samples are then analyzed for drug content to determine the rate and extent of dissolution. Such systems may be adequate for modeling dissolution within the GI tract, and especially the stomach cavity, where fluid turnover is minimal. Saliva, in contrast, is produced and swallowed continuously so that a closed vessel design does not accurately simulate the oral cavity.
Hughes (U.S. Pat. Pub. No. 2003/0087457) addresses dissolution of compounds in the buccal cavity prior to passage to the GI. The apparatus in Hughes suffers a drawback in that the interaction of dissolution medium with the solid compound does not realistically model dissolution of the solid in the oral cavity where all surfaces of the solid compound are exposed to dissolution fluid flow. In addition, the apparatus in Hughes is a relatively complex and expensive means for assessing dissolution comprising two outlet ports and an in-line dissolution analyzer. In addition, the dissolution medium is stirred, which inappropriately simulates the relatively gentle fluid movements in the oral cavity and requires larger dissolution fluid volumes to ensure immersion of the stirrer.
Li et al. (U.S. Pat. No. 6,004,822) describe a device to measure dissolution of solids in submilliliter quantities (10 to 400 microliters) of a solvent and correspondingly small amount of the solid. The device in Li unsatisfactorily models dissolution in the oral cavity because, in part, there is no flow-through cell, but rather it is a closed system. The solvent remains within the cell and is pumped between two chambers in fluid communication with one another. The oral cavity, in contrast, contains approximately 50 mL of saliva that is continuously replenished as saliva exits the oral cavity or is absorbed and/or broken down during solid dissolution.